The prevalence of nicotine dependence, its accompanying health problems, and the difficulty users have in maintaining abstinence combine to make it one of the most problematic abused drugs in our society. Clinical studies were designed to provide a better understanding of the pathophysiology and mechanisms of nicotine dependence as well as to contribute to the development of putative new smoking cessation treatments. Several nicotine delivery systems have been developed to aid in smoking cessation. Two of these, nicotine polacrilex and nicotine transdermal patches, have been approved for over the counter sales for this purpose. Currently new nicotine delivery systems developed for smoking cessation indications, including a nicotine nasal spray and a nicotinevapor inhaler are available as prescription items . These systems are notable for having a more rapid delivery rate, a factor that has been associated with greater potential for abuse. Therefore, although developed as aids for smoking cessation, such systems may be abused in their own right. The first study was designed to examine the physiological, subjective and performance effects of various doses of nicotine nasal spray and vapor inhaler compared to a regular cigarette, which served as a standard positive control. This placebo-controlled, double blind, outpatient study will provide needed information about the abuse liability of these products. The effects of cotinine, the major metabolite of nicotine, was evaluated as a treatment for tobacco withdrawal. This study was based on recent findings that cotinine administration induced subjective changes in abstinent human cigarette smokers. The purpose of the study was to characterize the pharmacodynamic effects of cotinine in cigarette smokers undergoing periodic abstinence, including symptoms of tobacco withdrawal, mood and subjective state, drug effect, performance, and endocrine effects. The pharmacodynamic and pharmacokinetic effects of a new treatment for tobacco withdrawal were studied in an outpatient protocol. We found that treating cigarettes with a corn syrup-based solution significantly reduced exposure to nicotine and CO. Further, the effects were similar in man and women. Pharmacokinetic effects of nicotine were similar in men and women indicating that gender differences in patterns of smoking and tobacco withdrawal are not due to kinetic differences in nicotine metabolism in men and women. In an on-going study the effects of befloxatone, a reversible MAO inhibitor is evaluated for smoking cessation therapy. In further studies of the denicotinized cigarettes, a preliminary evaluation of cigarettes is being conducted. In another study the denicotinized cigarettes are being used in a rapid smoking protocol.